1. Field of the Invention:
The present invention relates to the use of S(+) fenoprofen to elicit an onset-hastened and enhanced analgesic response in mammalian organisms in need of such treatment, and to certain pharmaceutical compositions comprising unit dosage effective amounts of S(+) fenoprofen.
2. Description of the Art:
Fenoprofen, also known as .alpha.-dl-2-(3-phenoxyphenyl)-propionic acid or (.+-.)-m-phenoxyhydratropic acid, has the structural formula ##STR1## The compound is well-known as a nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity. In the United States, fenoprofen is marketed as the calcium salt dihydrate under the tradename Nalfon.RTM.. Other tradenames or codenames for fenoprofen calcium salt dihydrate include Lilly 69323, Fenopron, Feprona, Nalgesic and Progesic. As Nalfon.RTM., the drug is available by prescription in amounts equivalent to 200 mg or 300 mg (capsules) or 600 mg (tablets) of fenoprofen. For the treatment of mild to moderate pain, 200 mg every four to six hours, as needed, is generally recommended. For rheumatoid arthritis and osteoarthritis, 300 to 600 mg three or four times a day is the recommended dosage, not to exceed 3200 mg daily. See also Physician's Desk Reference, 41st edition, 1987, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, N.J. 07649, pp. 890-891.
As is apparent from its chemical nomenclature, fenoprofen is a racemic mixture It is only the racemic mixture which has in fact ever been marketed. There have, however, been a few studies of the individual S(+) and R(-) isomers reported in the literature. These generally reflect that the R(-) isomer is rapidly converted to the S(+) enantiomer, which is the active form of fenoprofen.
Hutt et al, J. Pharm. Pharmacol., 35, 693-704 (1983), reviewed the earlier work on the metabolic chiral inversion of 2-arylpropionic acids, including ibuprofen, which they indicate was the first substituted 2-arylpropionic acid conclusively shown to undergo the inversion as well as the most studied member of the group. The authors noted that early workers found no significant difference in in vivo activity among the R(-) and S(+) isomers and the racemic mixture of ibuprofen in three different animal models, but very large differences in vitro between the R(-) and S(+) isomers, ascribing this discrepancy to the virtually quantitative conversion of the R(-) to the active S(+) isomer in vivo. Hutt et al indicated similar properties for fenoprofen. While no reports of the chiral inversion of fenoprofen had appeared at that time, the enantiomers of fenoprofen were reported to be of equal potency in animal test systems; moreover, it was noted that fenoprofen was known to undergo incorporation in triglycerides, an indirect indication of chiral inversion.
In the same paper, Hutt et al reported that, in contrast, for several other 2-arylpropionic acids, the inactive R(-) isomer was not converted in vivo to the active S(+) isomer as readily as ibuprofen and fenoprofen, although the conversion seemed to occur to some extent over time. Naproxen, they noted, has been the only compound marketed as the S(+) enantiomer to date. And in the case of indoprofen, the R(-) enantiomer was found to be about 20 times less pharmacologically active in rats and mice in vivo than the S(+) isomer. Hutt et al concluded:
It is likely that benefits will be obtained from the use of the S(+)-enantiomer of 2-arylpropionates as drugs as opposed to the racemates. This is only found at present in the case of naproxen. In cases of rapid inversion, the inactive R(-) isomer serves merely as a prodrug for the active S(+)-antipode. Where inversion is slow, the R(-) enantiomer is an unnecessary impurity in the active S(+) form. Use of the S(+)-enantiomer would permit reduction of the dose given, remove variability in rate and extent of inversion as a source of variability in therapeutic response and would reduce any toxicity arising from non-stereospecific mechanisms.
Thus, in cases of rapid inversion, such as ibuprofen and fenoprofen, where substantially equivalent in vivo responses have been reported for the individual enantiomers and the racemic drug, Hutt et al suggested that no benefits would be obtained from the use of the S(+) isomer because the inactive R(-) isomer merely acts as a prodrug for the active S(+) form. Contrariwise, in cases where chiral inversion is slow, e.g. naproxen and indoprofen, the use of the S(+) enantiomer is desirable for several reasons enumerated by Hutt et al. Indeed, naproxen has been reported to be marketed as the d-isomer for one of the reasons given by Hutt et al, i.e. to reduce side effects (Allison et al, "Naproxen," Chapter 9 in Anti-inflammatory and Anti-Rheumatic Drugs, eds. Rainsford and Path, CRC Press Inc., Boca Raton, Florida, 1985, p. 1 72).
Another general report on earlier work has been provided by Hutt et al in Clinical Pharmacokinetics, 9, 371-373 (1984). In this article on the importance of stereochemical considerations in the clinical pharmacokinetics of 2-arylpropionic acids, the authors tabulated relative potencies of the enantiomers of a number of 2-arylpropionic acids in vivo and in vitro The in vitro results showed the S or (+) isomer in each case to be the active species. In vivo, however, the results were not consistent across the entire class. Thus, the results for naproxen and indoprofen demonstrate the S on (+) isomer to be much more active in vivo, indicating a relatively slow inversion of the inactive R or (-) isomer to the active S or (+) isomer; the results for fenoprofen and ibuprofen, on the other hand, demonstrate the inactive R or (-) and the active S or (+) isomers to be approximately equally effective in vivo, indicating a rapid inversion of R or (-) isomer to S or (+) isomer. References for the fenoprofen test results cited by Hutt et al include Nicklander et al, Federation Proceedings 30, 563 (1971) and Rubin et al, J. Pharm. Sci. (in press, 1984). The Rubin et al reference, which was actually published in 1985, is discussed in detail below.
Rubin et al, J. Pharm. Sci. 74 (1), 82-84 (1985), studied the stereoselective inversion of R(-) fenoprofen to S(+) fenoprofen in healthy human volunteers. The authors administered the calcium salt of racemic fenoprofen orally and determined the amounts of R and S isomers in plasma and urine and the amounts of 4'-hydroxy metabolites in urine at various time points after administration. The R(-) isomer was found to be stereoselectively inverted to S(+), the major isomeric form found in plasma and urine. It was observed that 78-86% of administered fenoprofen racemate was recovered as S(+) fenoprofen plus the S-4'-hydroxy metabolite. In in vitro testing, the S enantiomer was found to be about 35 times as active at inhibiting cyclooxygenase as the R isomer and twice as active as the racemate. Rubin et al noted that earlier studies in the rat, mouse and guinea pig by Nicklander et al and others showed no difference in vivo in pharmacological and toxicological anti-inflammatory activities for the enantiomers, and indicated that those results may mean that the R(- ) isomer is inverted quickly to the S(+) isomer in animals, as in man. Since the earlier studies did not analyze plasma or urine for individual isomers, Rubin et al qualitatively analyzed urine from rats, mice and guinea pigs dosed with racemic fenoprofen and found the excreted drug forms to be almost totally of the S configuration.
Williams et al, Drugs 30,333-354 (1985), reviewed the importance of drug enantiomers in clinical pharmacology generally. With respect to fenoprofen, the authors noted Rubin et al's work (discussed above) as being flawed because only racemic drug was administered and thus relative clearances and fractions inverted were uncertain. Nevertheless, Rubin et al did demonstrate the apparent avidity of the inversion process for fenoprofen, which Williams et al cited as "an example of a drug for which total racemic drug concentrations are very similar to the concentration of the active drug."
The enantioselective disposition of fenoprofen in normal rabbits was studied by Hayball et al, J. Pharmacol. Exp. Ther., 240 (2), 631-636 (1987). These authors administered the R and S isomers of fenoprofen separately as well as the racemic mixture. Blood samples were collected before and at about 0.25, 1, 3, 5, 7, 10, 15, 20, 25, 30 minutes, then at 15 minute intervals until 120 minutes after dosing with S(+) fenoprofen. Similar time points were selected for R(-) and racemic fenoprofen blood samples. No S to R inversion was noted, but at two hours an average of 73% of R was inverted to S, although large interanimal variations (from 30.4 to 100%) were noted. The authors noted that their bound plus unbound fenoprofen concentration data had its limitations; if fenoprofen enantiomers bind to rabbit plasma stereoselectively, then their estimates of the clearance and distribution of the individual enantiomers would be biased. While there is no clear literature on whether fenoprofen exhibits stereoselective binding, it is quite likely that it does. It would have been desirable to measure unbound fenoprofen; unfortunately, the assay methodology was not of sufficient sensitivity to allow such measurements.
In summary, the current state of the art recognizes that, in mammals, the S(+) form is the active enantiomer of fenoprofen. The art further recognizes that there is a significant, relatively rapid conversion in vivo of R(-) to S(+), with no noted conversion of S(+) to R(-). Furthermore, in the only animal experiments on efficacy reported in the literature, it was noted that there were no significant differences in potency between the racemate and the enantiomers. This is attributed to the rapidity of the chiral inversion. This would suggest there would be no benefit to be derived from the use of S(+) fenoprofen alone for analgesia. The prior art, moreover, is conspicuously silent in respect to any onset-hastened/enhanced alleviation of mammalian pain utilizing whatever form of the fenoprofen drug species.